Document: spc-doc_PL 36390-0141 change

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• spc-doc_PL 36390-0141

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Fluconazole 200 mg capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 200 mg fluconazole.

Excipient with known effect:

Each capsule contains 149.28 mg of lactose monohydrate (see section 4.4) For a full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Hard capsules

Size 0 hard gelatin capsules, dark blue opaque cap and white body: marked with the code ‘FCZ 200’

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

Fluconazole 200 mg Capsules are indicated for the treatment of the following conditions when caused by fungi that are known or are likely to be fluconazole-susceptible:

1.    Genital candidiasis. Vaginal candidiasis, acute or recurrent. Candidal balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.

2.    Mucosal candidiasis. These include oropharyngeal, oesophageal, noninvasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.

3.    Systemic candidiasis including candidaemia, disseminated candidiasis and other forms of invasive candidal infection. These include infections of theperitoneum, endocardium and pulmonary and urinary tracts. Candidal infections in patients with malignancy, in intensive care units or those receiving cytotoxic or immunosuppressive therapy may be treated.

4.    For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.

5.    Cryptococcosis, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts, and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.

6.    Tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections. Fluconazole is not indicated for nail infections and tinea capitis.

Consideration should be given to official guidance on the appropriate use of antifungal agents.

4.2 Posology and method of administration

For oral use.

The daily dose of Fluconazole Capsules should be based on the nature and severity of the fungal infection. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has responded. An inadequate period of treatment may lead to recurrence of active infection.

Use in adults

1.    Candidal vaginitis or balanitis: 150 mg single oral dose.

2.    Mucosal Candidiasis:

Oropharyngeal candidiasis: the usual dose is 50 mg once daily for 7 - 14 days. Treatment should not normally exceed 14 days except in severely immunocompromised patients.

For atrophic oral candidiasis associated with dentures - the usual dose is 50mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.

For other candidal infections of mucosa except genital candidiasis (see above), e.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50 mg daily, given for 14 - 30 days.

In unusually difficult cases of mucosal candidal infections the dose may be increased to 100 mg daily.

3.    For candidaemia, disseminated candidiasis and other invasive candidal infections the usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response the dose may be increased to 400 mg daily. Duration of treatment is based upon the clinical response.

4.    For the prevention of Candida infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 50 to 400 mg once daily, based on the patient's risk for developing fungal infection. For patients at high risk of systemic infection, e.g. patients who are anticipated to have profound or prolonged neutropenia such as during bone marrow transplantation, the recommended dose is 400 mg once daily. Fluconazole administration should start a few days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per mm³.

5a.For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400 mg on the first day followed by 200 mg - 400 mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis.

5b.A 100 mg - 200 mg daily dose is recommended to prevent recurrence of cryptococcal meningitis. Duration of maintenance treatment in AIDS patients should be carefully justified because of the increased risk of resistance to fluconazole.

6. Verified fungal skin infections: tinea pedis, corporis, cruris, versicolor and dermal candida infections the recommended dosage is 50 mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.

Use in children

As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum daily dose in children is 400 mg as a single daily dose and this should not be exceeded.

The capsules are not suitable for children who cannot take oral medication. Also, the required dose in mg/kg (see below) often cannot be achieved with capsules.

For children with impaired renal function, see dosing in "Use in patients with impaired renal function".

Children over four weeks of age

The recommended dose of Fluconazole Capsules for mucosal candidiasis is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly.

For the treatment of systemic candidasis and cryptococcal infections, the recommended dosage is 6-12 mg/kg daily, depending on the severity of the disease.

For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3-12mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).

Despite extensive data supporting the use of fluconazole in children there are limited data available on the use of fluconazole for genital candidiasis in children below 16 years. Use at present is not recommended unless antifungal treatment is imperative and no suitable alternative agent exists.

The administration of Fluconazole Capsules is unsuitable for doses less than 50 mg. To facilitate accurate measurement of doses less than 50 mg, alternative oral suspension or intraveneous infusion formulations should be used.

Children four weeks of age and younger

The administration of Fluconazole Capsules is unsuitable for these patients. To facilitate accurate measurement of doses less than 10 mg, fluconazole should only be administered to children in hospital using alternative oral suspension or intravenous infusion formulations.

Use in the elderly

The normal dose should be used if there is no evidence of renal impairement. In patients with renal impairment (creatinine clearance less than 50 ml/min) the dosage schedule should be adjusted as described below.

Use in patients with impaired renal function

Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients (including children) with impaired renal function who will receive multiple doses of fluconazole, the normal recommended dose for the indication should be given on day 1, followed by a daily dose according to the following table:

Creatinine clearance (ml/ min)	Percent of recommended dose
>50 <50 (no dialysis) Regular dialysis	100% 50% 100% after each dialysis

Method of Administration

Fluconazole Capsules should be swallowed whole and may be taken without regard to meals.

The route of administration depends on the clinical condition of the patient. It is not necessary to change the daily dose of fluconazole when changing the route of administration from intravenous to oral.

4.3 Contraindications

Fluconazole must not be used:

In patients with known hypersensitivity to fluconazole or to related triazole antifungal agents or to any other ingredient in the formulation (see section 6.1).

Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride or astemizole pimozide and quinidine are contraindicated in patients receiving fluconazole (see section 4.4 and 4.5).

4.4 Special warnings and precautions for use

Tinea capitis

Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, fluconazole should not be used for tinea capitis.

Cryptococcosis

The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.

Deep endemic mycoses

The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations.

Hepatobiliary system

Fluconazole should be administered with caution to patients with liver dysfunction.

Cardiovascular system

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarryhthmic conditions. Therefore, fluconazole should be used with caution in patients with congenital or documented acquired QT prolongation, electrolyte disturbance (particularly in hypokalaemia and hypomagnesemia) and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5) and in patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

Halofantrine

Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5).

If concomitant administration with medicinal products that are known to induce QT interval prolongation such as antiarrhythmics of class IA and III is necessary, the patient must be closely monitored, including ECG monitoring. Concomitant treatment with cisapride, or astemizole is contraindicated (see section 4.3 and 4.5).

Terfenadine

The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 Contraindications and 4.5 Interaction with Other Medicaments and Other Forms of Interaction).

Cytochrome P450

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window (e.g. warfarin and phenytoin) metabolised through CYP2C9 and CYP3A4, should be monitored (see section 4.5 Interaction with Other Medicaments and Other Forms of Interaction). In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed during treatment with fluconazole but the clinical significance and relationship to treatment is uncertain.

Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions.

Very rarely, patients who died with severe underlying disease and who had received multiple doses of fluconazole had post-mortem findings which included hepatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic, and/or had underlying diseases which could have caused the hepatic necrosis

In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose of fluconazole, duration of therapy, sex or age of the patient has been observed; the abnormalities have usually been reversible on discontinuation of fluconazole therapy.

As a causal relationship with fluconazole cannot be excluded, patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms (important asthenia, anorexia, persistent nausea, vomiting and jaundice) consistent with liver disease develop during treatment with fluconazole that may be attributable to fluconazole and the patient should consult a physician.

Dermatological reactions

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens - Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs. If a rash develops in a patient treated for a superficial fungal infection which is considered attributable to fluconazole, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity

In rare cases, as with other azoles, anaphylaxis has been reported (see section 4.8).

Renal system

Fluconazole should be administered with caution to patients with renal dysfunction. The dose of fluconazole must be reduced when creatinine clearance is below 50 ml/min (see section 4.2).

There is limited experience with long-term administration of doses higher than

1-200 mg daily.

Excipients

Lactose intolerance: Since the capsules contain lactose, they should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction with other medicinal products and other forms of interaction

The following combinations are contra-indicated:

Cisapride (CYP3A4 substrate): There have been reports about cardiac cases including Torsades de pointes in patients receiving fluconazole concomitantly with cisapride. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QT interval. Concomitant treatment with fluconazole and cisapride is contraindicated. (see section 4.3)

Terfenadine (CYP3A4 substrate): Due to the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc-interval in patients receiving azole antifungal drugs concomitantly with terfenadine, interaction studies have been performed. One study with 200mg fluconazole daily did not show any prolongation of the QTc-interval. Another study with 400mg and 800mg fluconazole daily showed that fluconazole 400mg or more daily significantly increases the plasma level of terfenadine when taken concomitantly. Concomitant treatment with terfenadine and fluconazole at doses of 400 mg or greater is contra-indicated. (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terefenadine should be carefully monitored.

Astemizole (CYP3A4 substrate): Concomitant administration of fluconazole: with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of¹ torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Therefore, coadministartion of fluconazole and pimozide is contraindicated.

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see section 4.3).

Erythromycin: Concomitant use of Fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, Torsades de Pointes) and consequently sudden death. This combination should be avoided.

Concomitant use of the following other medicinal products cannot be recommended:

Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4).

Concomitant use of the following other medicinal products lead to precautions and dose adjustments:

Effect of fluconazole on the metabolism of other medicinal products:

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the isozyme CYP2C19. Besides the observed/documented interactions listed below there is a risk of increased plasma concentrations of other compounds metabolised by CYP2C9 and CYP3A4 (e.g. ergot-alkaloids,) when co-administered with fluconazole. Therefore, care should always be taken when using these combinations and the patients should be carefully monitored. The enzyme-inhibiting effect of fluconazole may persist for 45 days after end of fluconazole treatment due to the long fluconazole halflife (see section 4.3).

Alfentanil (CYP3A4 substrate): A study observed that concomitant intake of fluconazole and alfentanil resulted in decreased - clearance by and distribution volume as well as prolongation of T1/2 of alfentanil. A possible mechanism of action is fluconazole’s inhibition. During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20pg/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4. Adjustment of the alfentanil dose may be required.

Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitnptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary

Amphotericine B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Anticoagulants (CYP2C9 substrate): In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole anti-fungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. Prothrombin times must be closely monitored in patients on treatment with coumarin derivatives. Dose adjustment of warfarin may be necessary.

Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction

between fluconazole and azithromycin.

Benzodiazepines (Short acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects.. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If it is necessary to treat patients with a benzodiazepine concomitantly with fluconazole, a reduction of the benzodiazepine dose should be considered and the patients should be closely monitored.

Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole.Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C_max with 20-32% and increases t1/2 by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effects.

Calcium channel antagonists (CYP3A4 substrates): Some dihydropyridine calcium channel antagonists (including nifedipine, isradipine, amlodipine, and felodipine) are metabolised via CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Celecoxib (CYP2C9 substrate): Concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) resulted in a 68% and 134% increase in celecoxib Cmax and AUC, respectively. Halving the Celecoxib dose is recommended in patients concurrently treated with fluconazole.

Ciclosporin (CYP3A4 substrate): Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

Cyclophosphamide: combination therapy with cyclophosphamide results

in increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore. in a randomized crossover study with twelve healthy volunteers

it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

HMG-CoA reductase inhibitors (CYP2C9 or CYP3A4 substrates): The risk of myopathy and rhabdomyolysis is increased when fluconazole is administered concurrently with HMG CoA reductase inhibitors that are metabolised via CYP3A4, such as atorvastatin and simvastatin, or via CYP2C9, such as fluvastatin. Caution is warranted if concurrent administration of fluconazole and HMG-CoA reductase inhibitors is deemed necessary. Patients should be monitored for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness or weakness) and creatine kinase (CK) levels. HMG-CoA therapy should be discontinued if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected.

Losartan (CYP2C9 substrate): Fluconazole inhibits the conversion of losartan to its active metabolite (E-3174), which is responsible for a large part of the angiotensin II receptor antagonism that occurs with losartan therapy. It is recommended that patients receiving the combination be monitored for continued control of their hypertension.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs: The C_max and AUG of flurbiprofen was increased by 23% and 81 %, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C_max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Oral contraceptives: Two pharmacokinetic studies have been performed with a combined oral contraceptive and multiple dosing of fluconazole. 50 mg fluconazole did not influence any of the hormone concentrations, but 200 mg daily increased AUC ethinylestradiol and levonorgestrel by 40% and 24%, respectively. Thus, multiple dosing of fluconazole at these doses is unlikely to impair the efficacy of combined oral contraceptive pills.

Phenytoin (CYP2C9 substrate): Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC 24 by 75% and C_min by 128%.With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Prednisone (CYP3A4 substrate): A liver transplant recipient receiving prednisone experienced an Addisonian crisis when a three-month course of fluconazole was discontinued. The withdrawal of fluconazole was likely to have caused an increase in CYP3A4 activity, leading to an increase in the degradation of prednisone. Patients receiving long-term therapy with fluconazole and prednisone should be closely monitored for signs of adrenal cortex insufficiency when fluconazole is withdrawn.

Rifabutin (CYP3A4 substrate): Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of 80%. Uveitis in patients treated concomitantly with fluconazole and rifabutin has been reported. Patients who receive rifabutin and fluconazole concomitantly must be closely followed for symptoms of rifabutin toxicity.

Saquinavir: Fluconazole increases the AUC of saquinavir with approximately 50%, Cmax with approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P- glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Sulphonylureas (CYP2C9 substrate): It has been demonstrated that fluconazole prolongs the plasma half-life of concomitantly administered oral sulphonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration

Tacrolimus (CYP3A4 substrate): Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Theophylline: In a placebo controlled interaction study, intake of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients being treated with high doses of theophylline or with any other reason to be at increased risk of theophylline toxicity should be observed carefully during concomitant treatment with fluconazole and the dose of theophylline must be adjusted as necessary.

Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole. CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Voriconazole: (CYP2C9 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in C_max and AUC_X of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90%

CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole.

Zidovudine: Fluconazole increases C_max and AUC of zidovudine by 85% and 75%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The halflife of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

Medicinal products affecting the metabolism and/or excretion of fluconazole:

Hydrochlorothiazide: In a pharmacokinetic interaction study with healthy volunteers who concomitantly received fluconazole and multiple doses of hydrochlorothiazide the plasma concentrations of fluconazole increased by 40%. An effect of this size should not necessitate a change in the fluconazole dose regimen in patients who are concomitantly treated with diuretics, although the prescriber should bear this in mind.

Rifampicin (CYP45O inducer): Concomitant intake of fluconazole and rifampicin resulted in a 25% reduction of AUC and 20% reduction in the half- life of fluconazole. An increase in the dosage of fluconazole should be considered in patients concomitantly receiving rifampicin.

Interaction studies have shown that no clinically significant change in absorption of fluconazole occurs with oral use together with food, cimetidine, antacids or after radiation therapy of the whole body in connection with bone marrow transplantation.

4.6 Fertility, pregnancy and lactation

Pregnancy

Data from a few hundred pregnant women treated with standard doses (< 200 mg/day) of fluconazole during early pregnancy do not indicate any undesirable effects on the foetus. There are reports of multiple congenital abnormalities in children whose mothers were treated for 3 months or longer with high doses (400-800 mg/day) of fluconazole for coccidioidal mycosis. The relation between these effects and treatment with fluconazole is not clear.

Studies in animals have shown teratogenic toxicity (see section 5.3). Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary. Fluconazole in high dose and/or in prolonged regimens should only be used during pregnancy in patients with serious or potentially life-threatening fungal infections and when the expected benefit to the mother has been weighed against the potential risk to the foetus.

Lactation

Fluconazole passes into breast milk to reach concentrations lower than those in plasma. Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. The use of fluconazole is therefore not recommended in breast feeding woman after repeated use or after high dose fluconazole.

Fertility

Fluconazole did not affect the fertility of male or female rats (see section 5.3)

4.7 Effects on ability to drive and use machines

No studies have been performed on the effects of fluconazole on the ability to drive or use machines. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur and patients should be advised not to drive or operate machines if any of these symptoms occur.

4.8 Undesirable effects

Fluconazole is generally well tolerated.

The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results as hepatic abnormalities (see section 4.4) have been observed during the treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

The following undesirable effects have been observed and reported during the treatment with fluconazole with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000, < 1/100), rare (>1/10000, < 1/1000) and very rare (>1/10000), not known (cannot be estimated from the available data).

System Organ Class	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000
Blood and lymphatic system disorders		Anaemia	Agranulocytosis, leucopenia, neutropenia, thrombocytopenia
Immune system disorders			Anaphylaxis
Metabolism and nutrition disorders		Decreased appetite	Hyp erchol ester ol aemi a , hypertriglyceridaemia, hypokalaemia
Psychiactric disorder		Insomnia, somnolence
Nervous system disorders	Headache	Seizures, dizziness, paraesthesia, taste perversion	Tremor
Ear and labyrinth		Vertigo

disorders
Cardiac disorders			Torsade de pointes(see section 4.4), QT prolongation(see section 4.4)
Gastrointestinal disorders	Abdominal pain, diarrhoea, nausea, vomiting	Dyspepsia, constipation, flatulence, dry mouth
Hepato-biliary disorders	Alanine aminotransferase increased(see section 4.4), aspartate aminotransferase increased(see section 4.4), blood alkaline phosphatase increased(see section 4.4)	Cholestasis(see section 4.4), jaundice(see section 4.4), bilirubin increased(see section 4.4)	Hepatic failure(see section 4.4), hepatocellular necrosis(see section 4.4) , hepatitis(see section 4.4), hepatocellular damage(see section 4.4)
Skin and subcutaneous tissue disorders	Rash(see section 4.4)	Pruritus, urticaria(see section 4.4), increased sweating, drug eruption(see section 4.4)	Toxic epidermal necrolysis (see section 4.4) , Stevens- Johnson syndrome(see section 4.4) , acute generalised exanthematouspustulos is(see section 4.4), dermatitis exfoliative, angioedema, face
Musculoskeletal, connective tissue and bone disorders		Myalgia	oedema, alopecia
General disorders and administration site conditions		Fatigue, malaise, asthenia, fever

Paediatric Population

The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There have been reports of overdose with fluconazole and hallucination and paranoid behaviour have been concomitantly reported.

In the event of overdose, symptomatic treatment (with supportive measures and with gastric lavage if necessary), may be adequate.

As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC code: JO2A C01. Antimycotics for systemic use; triazole derivatives.

Fluconazole belongs to the group of triazole antimycotics, specifically inhibiting fungal ergosterol synthesis by specific inhibition of the mycotic cytochrome P-450 enzymes. It has a fungistatic effect

Fluconazole shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbital sleeping times in mice (p.o.), increased mean arterial and left ventricular blood pressure and increased heart rate in anaesthetised cats (i.v.) occurred. Inhibition of rat ovarian aromatase was observed at high concentrations.

Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp. including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum spp. and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitides; with Coccidoides immitis, including intracranial infection and with Histoplasma capsulatum in normal and immunosuppressed animals.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy.

Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50mg do not affect its metabolism.

The efficacy of fluconazole in tinea capitis has been studied in 2 randomised controlled trials in a total of 878 patients comparing fluconazole with griseofulvin. Fluconazole at 6 mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11 mg/kg/day for 6 weeks. The overall success rate at week 6 was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin: 17.7%) across all treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of fluconazole are identical after intravenous and oral administration.

After oral administration fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by day 4 -5 with multiple once daily dosing.

Plasma concentration is proportional to the dose:

-    after administration of 200mg of fluconazole, C_max is around 4.6 mg/l and plasma concentrations obtained at steady-state after 15 days are around 10mg/l.

-    after administration of 400mg of fluconazole, C_max is around 9mg/l and plasma concentrations obtained at steady-state after 15 days are around 18mg/l.

Intake of a double dose on day 1 results in plasma concentrations that are approximately 90% of steady state on day 2.

Distribution:

The volume of distribution corresponds to the total body water. The protein binding in plasma is low (11-12%).

Fluconazole is distributed over the total body water. The concentration in saliva corresponds to the plasma concentration. In patients with fungal meningitis the concentration of fluconazole in the cerebrospinal fluid is approximately 80% of the corresponding plasma concentration.

In stratum corneum, epidermis-dermis and in exocrine sweat higher concentrations of fluconazole are reached compared to those in serum. Fluconazole is accumulated in stratum corneum. At a dose of 150mg once weekly the concentration of fluconazole in stratum corneum was after 2 doses 23.4pg/g and 7 days after the second dosing it was still 7.1 pg/g.

Elimination

The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.

The long plasma elimination half-life (approximately 30 hours) provides the basis for single dose therapy for genital candidiasis and once daily dosing for other indications.

Children metabolise fluconazole more rapidly. Accordingly the half-life in children of 5 - 15 years is between 15.2 - 17.6 hours, about half of that in adults.

It has been demonstrated that fluconazole 50 mg daily given for up to 28 days does not influence plasma concentrations of testosterone in men or steroidal hormone concentrations in women of childbearing age. Fluconazole 200 -400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated responses in healthy, male volunteers.

5.3 Preclinical safety data

Preclinical data from conventional studies on repeat-dose/general toxicity, genotoxicity or carcinogenicity indicate no special hazard for humans not already considered in other sections of the SPC.

In reproduction toxicity studies in rat an increased incidence of hydronephrosis and extension of renal pelvis was reported and embryonal lethality was increased. An increase in anatomical variations and delayed ossification was noted as well as prolonged delivery and dystocia, effects consistent with inhibition of oestrogen synthesis in rat. In reproduction toxicity studies in rabbits abortions were recorded. These effects were observed only at exposures in excess of the maximum human exposure.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule contents: lactose monohydrate, maize starch, colloidal anhydrous silica, talc, sodium lauryl sulphate.

Capsule shells: gelatin, patent blue (E131), titanium dioxide (E171), Ponceau 4R (E124), indigo carmine (E132).

Printing ink: black iron oxide (E172), shellac, propylene glycol, dehydrated alcohol, isopropyl alcohol, butyl alcohol, strong ammonia solution, potassium hydroxide.

10 DATE OF REVISION OF THE TEXT

16/12/2014